PDF lowering LDL cholesterol and CrP levels "

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CARDIOVASCULAR JOURNAL OF AFRICA ? Vol 24, No 2, March 2013

AFRICA

6th World Congress Paediatric Cardiology and Cardiac Surgery Cape Town, February 2013

Satellite symposium

Consequences of underlying infection complicate CVD management in Africa

Patients in Africa with a high risk of coronary artery disease (CAD) often have elevated levels of C-reactive protein due to inflammation caused by infections. Additionally, this underlying inflammation produces significant platelet dysfunction in people who have the added complication of diabetes. Each of these complications and their therapeutic consequences were discussed by a distinguished faculty at a symposium titled: Unmasking cardiovascular complications: what are we missing?

`Any infection creates a risk of myocardial infarction (MI) because bursts of inflammation

in many trials; most of them have however been negative', Prof L?scher said.

By contrast, the evidence for lowering

terol and CRP levels. In this trial, 17 000 men and women were randomly assigned to rosuvastatin 20 mg or placebo and fol-

destabilise arterial plaques. A high rate of LDL cholesterol is consistent, and the lowed up for up to five years until the

infectious diseases resulting in high pre- message for both primary and secondary occurrence of a myocardial infarction,

vailing C-reactive protein (CRP) levels in prevention is `the lower the LDL level, the stroke, cardiovascular-related hospital

Africa, together with social deprivation, better the outcome'.

admission or cardiovascular death. Partici-

hypertension, diabetes and renal disease

`Also at the level of the coronary pants in the trial had low-to-normal LDL

add to the coronary artery disease (CAD) plaque, lowering LDL cholesterol levels cholesterol levels (3.4 mmol/l) and raised

risk in these individuals.' This view was as far as possible achieves better results. CRP levels of 2 mg/l or higher.2

expressed by Prof Thomas F L?scher, head This was clearly shown in the ASTEROID

`There was a marked reduction in

of Cardiology, University of Zurich and trial with rosuvastatin where intensive cardiovascular events in patients receiving

current editor-in-chief of the European therapy led to an actual regression of rosuvastatin therapy and the size of this

Heart Journal.

atherosclerosis', he explained.

reduction was more than expected from

`Supportive evidence for this view on

JUPITER, the most important trial of the statistical modelling', Prof Luscher

infections comes from studies in patients lipids in primary prevention, also high- said (Fig. 1).

with long-term rheumatoid arthritis,1 lighted the value of lowering LDL choles-

`The JUPITER data have also proved to be

where treating these patients

invaluable in the interpretation

with simvastatin improved

of the recent finding that statin

vascular function considerably.

therapy can increase patient's

This vascular benefit can also

overall risk of diabetes', Prof

be attributable to reduced

Luscher said, referring to the

levels of CRP and other

recently published evaluation

inflammatory cytokines', Prof

which showed that among the

L?scher pointed out.

primary-prevention patients

Low-density lipoprotein

included in the JUPITER

(LDL) cholesterol is the main

study, the cardiovascular and

target for addressing the lipid-

mortality benefits of statin

related risk of cardiovascular

therapy far exceeded the

events, with added benefit to

diabetes hazard, even in study

be derived from also address-

participants who were at high

ing CRP levels. `The potential

risk of developing diabetes.3

benefit of targeting high-den-

Nevertheless, plasma glucose

sity lipoprotein (HDL) choles- Fig. 1. JUPITER trial endpoint: myocardial infarction, stroke, UA/revascularisa- level needs to be monitored in

terol has also been investigated tion, cardiovascular death.

patients on statin treatment.

"

Jupiter . . . highlighted the value of lowering LDL cholesterol and CRP levels

"

AFRIC A CARDIOVASCULAR JOURNAL OF AFRICA ? Vol 24, No 2, March 2013

45

New era in antiplatelet therapy

Is clopidogrel adequate in 2013?

In reviewing oral anti-platelet therapy for acute coronary syndromes today, clinicians would most likely demand

Dr Stephen Wheatcroft

that any acceptable therapy meet at least

three criteria and provide:

? rapid onset of action

? reproducible and reliable inhibition

of platelet activation

? acceptable risk of bleeding.

Adhering to today's standard, Dr Ste-

phen Wheatcroft, consultant inter-

ventional cardiologist at the University

of Leeds noted that his Unit now uses clopidogrel requires a two-step bio-

ticagrelor across the board for acute transformation in the liver to its active

coronary syndrome (ACS) patients, both metabolite, thereby allowing genetic

STEMI and NSTEMI patients. `There is no polymorphisms to influence the reliability

doubt that clopidogrel is a good drug, of the antiplatelet response. Ticagrelor is

as shown in the CURE study. However, direct acting and its effect is independ-

there is also a good evidence base for ent of genetic polymorphisms, ensuring

the new agents, prasugrel and tica- a consistent inhibition of platelet activity.

grelor, and the latter offers significant

Ticagrelor also produces a greater

advantages over clopidogrel', he noted. inhibition of platelet aggregation than

In terms of today's criteria, ticagre- clopidogrel. The more reliable platelet

lor has a faster onset of action than the inhibition with ticagrelor (180 mg load-

other agents, as it is direct acting and ing dose, then 90 mg bid) was seen

does not require in vivo

biotransformation. An

active metabolite is also

formed which contributes

in part to ticagrelor's clini-

cal effect.

Reproducible and reli-

able platelet inhibition

is not a characteristic of

the clinical experience

with clopidogrel. `Low

responders are exposed to

a doubled risk of adverse

events compared to those

ACS patients who respond

well to clopidogrel', Dr

Wheatcroft pointed out.

One of the reasons

for the heterogeneity of

platelet inhibition is that Fig. 2. PLATO main endpoints.

in the PLATO results where ticagrelor significantly reduced the combined endpoints of cardiovascular death, myocardial infarction and stroke.

`Importantly, the overall risk reduction was not only driven by a myocardial infarction rate reduction as was the experience in the CURE study, but also by a reduction in cardiovascular death and all-cause mortality (Fig. 2). `While the overall risk of experiencing an event was higher in medically managed patients who formed 36% of the total PLATO cohort, ticagrelor treatment also reduced the composite endpoints in this important group of patients', Dr Wheatcroft noted.

Finally, in terms of today's third criteria of safety, the additional benefits of ticagrelor did not come at the price of increased bleeding, as there was no significant difference in major bleeding rates between the clopidogrel- and ticagrelor-treated patients in the PLATO study (Fig. 2). Non-coronary artery

bypass graft (CABG)related major bleeds were more common in ticagrelor-treated patients, while CABG-related bleeding rates were similar with both agents.

While dyspnoea is an important side effect, it is typically mild, resulting in a less than 1% discontinuation rate in the PLATO study. `In our own clinical experience, this dyspnoea is certainly mild and transient and, with appropriate reassurance, patients can continue with the medication', Dr Wheatcroft concluded.

" There is a good evidence base . . . that ticagrelor offers significant advantages

over clopidogrel

"

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CARDIOVASCULAR JOURNAL OF AFRICA ? Vol 24, No 2, March 2013

AFRICA

Achieving glycaemic control

Incretins: cardiovascular safety and rationale for use

T he majority of type 2 diabetes patients die from cardiovascular events with MI and stroke being responsible for 75% of the increased mortality seen in diabetic patients. `One of the most important interpretations of the UKPDS trial4 of newly diagnosed patients and that of the STENO II trial5 of recently diagnosed type 2 diabetes patients is that the earlier you can treat the patient, the better the outcome, and then you can achieve a reduction in MI events over time', Dr Adri Kok, Johannesburg physician noted.

`The failure of our current diabetes treatment is that we do not achieve adequate glycaemic control. The incretins, with their weight-loss or weight-neutral effects are able to add to our HbA1c-lowering efficiency without causing hypoglycaemia or further side effects in patients who are already taking multiple therapies', she said.

Dr Adri Kok

Giving a snapshot view of the GLP-1 agonist injectables, exenatide and liraglutide, followed by the oral DPP-4s (vildagliptin, sitagliptin and saxagliptin), Dr Kok noted that their usefulness has been shown in a wide range of type 2 diabetes patients on both oral and insulin therapy. `While we do not yet have clinical trials designed to show effects on cardiovascular outcomes, there have been studies on all the incretins that indicate a cardiovascular

risk reduction',6 Dr Kok said. This finding has led to a study-generating hypothesis which is currently being evaluated in the SAVOR-TIMI53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes-thrombolysis in Myocardial Infarction).

Dr Kok noted that the 2012 SEMDSA guidelines for type 2 diabetes management support the early use of the oral DPP-4 inhibitors in combination with metformin.

`It is important to discuss with your diabetic patients their cardiovascular risk, explaining the important benefits and advantages of these incretin-based therapies as alternative to other agents such as the sulphonylurea and thiazolidinedione groups of drugs. The total cardiovascular risk of the patient with type 2 diabetes must be addressed with strict glucose control early in the course of the disease to avoid micro- and macrovascular complications later on', Dr Kok concluded.

References

1. Tikiz C, Utuk O, Pirildar T, Bayturan O, et al. Effects of ACE inhibition and statin treatment on inflammatory markers and endothelial functions in patients with long-term rheumatoid arthritis. J Rheumatoid Arthritis 2005; 32(11): 2095?2101.

2. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Eng J Med 2008; 359(21): 2195?2207.

3. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380(9841): 565?571.

4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837?853.

5. Gaede P, Lund-Andersen H, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes 2008; 358(6): 580?591.

6. Cobble ME, Frederich R. Saxagliptin for the treatment of type 2 diabetes mellitus assessing cardiovascular data. Cardiovasc Diabetol 2012; 10.1186/1475-2840-11-6.

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The failure of our current diabetes treatment is that we do not achieve

adequate glycaemic control

"

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